I. Core Research Summary

• Biomimetic Mechanical Three-Dimensional Nanoscale Drug-Eluting Coating

OPMSC self-assembles into a 150–200 nm spherical nanonetwork; at a 20% OP loading, the hydrogel exhibits a Young’s modulus comparable to that of brain tissue (on the order of hundreds of kPa), while its nanoscale rough surface enhances neural tissue integration. A hydrogen-bond crosslinking network confers resistance to enzymatic degradation in vitro for up to six months, ensuring long-term stability.

• Dual‑functional biointerface: anti‑adhesion + sustained‑release anti‑inflammation

The zwitterionic chitosan substrate exhibits robust anti‑fouling properties, markedly inhibiting the adhesion of astrocytes and microglia. It encapsulates natural OP‑derived antioxidant and anti‑inflammatory agents, with a high 20% loading ratio that ensures a gentle, sustained release—without an initial burst—continuously scavenging cellular reactive oxygen species and suppressing inflammatory signaling pathways.

• Precise Partitioned Patterning of Aerosols

Selectively, the OPMSC coating is deposited only in the insulating regions of the probe, leaving the gold electrode sites fully exposed and thus preserving neural signal acquisition; 30-μm micro‑lines are precisely fabricated, and a nanogel stack forms a continuous three-dimensional porous film, with robust interfacial adhesion that remains intact after washing.

• In vivo implantation significantly improves long-term recording performance.

Intracranial implantation in rats with 28-day continuous monitoring: the OPMSC‑coated probe exhibited lower interfacial impedance, a 40% increase in the number of detected neural units, and significantly reduced signal‑to‑noise ratio degradation compared with the uncoated control group. Immunofluorescence analysis revealed a marked decrease in the expression of activated microglia (ED1) and astrocytes (GFAP) around the probe, along with a significant increase in the number of surviving neurons (NeuN).

• A mild, low-temperature aerosol process preserves drug activity.

The entire process employs room-temperature atomization deposition, avoiding high temperatures and harsh acid–alkali treatments. As a result, the natural antioxidant components of OP remain intact, fully preserving their anti-inflammatory and ROS-scavenging bioactivities.

II. Core Operating Principle and Unique Technology of Aerosol Spraying

(1) Complete Neural Probe Coating Printing Process

• Pre‑treatment and cleaning of flexible PI neural probes, followed by surface plasma activation to enhance interfacial adhesion;
• Ultrasonic atomization of OPMSC nanogel dispersion, with nitrogen as the carrier gas and a coaxial sheath gas for precise jet‑beam confinement;
• Set the print area in CAD to deposit only on the probe’s insulating substrate, leaving the electrode areas unprinted.
• The airflow focusing ratio is regulated (FR ≥ 5), and nanoscale droplets undergo layer-by-layer hydrogen-bonding stacking to form a three-dimensional porous film.
• Cures by natural crosslinking at room temperature, eliminating the need for high-temperature baking; the finished product undergoes pure‑water rinsing tests to verify its stability.

(II) Five Core Process Advantages (Compared with Spin Coating, Dip Coating, and Photolithography Lamination)

• Selective Partition Patterned Printing

Dip coating and spin coating result in complete coverage of the probes, with the conductive electrodes encapsulated by an insulating gel, thereby losing their ability to acquire signals. In contrast, aerosol‑based digital zone‑direct writing deposits a protective film over the insulating regions while leaving the electrodes exposed, achieving functional patterning in a single step.

• Gentle deposition at room temperature, preserving bioactive drugs.

No high-temperature sintering, no chemical etching; the natural OP anti-inflammatory molecules remain intact and retain their activity, making them compatible with a wide range of protein-, polyphenol-, and peptide-based bio‑drug‑loaded inks.

• Controllable Fabrication of Three-Dimensional Porous Nanostructures

By focusing the airflow and modulating the gel‑stacking density, a biomimetic thin film with nanoscale roughness is precisely fabricated, simultaneously ensuring tissue conformity and providing a sustained drug‑release pathway.

• Non-contact microscale high-precision forming

Minimum print line width: 30 μm; compatible with micron-scale, ultra-thin neural probes; the ultrathin coating does not increase the probe’s overall volume, thereby reducing mechanical trauma during implantation.

• Consumable savings and rapid prototyping iterations

Localized nano‑gel deposition on demand, eliminating the need for full‑area coating; CAD‑based one‑click modification of the print layout enables rapid comparative testing of coatings with varying drug‑loading concentrations.

III. Five Core Technological Innovations of This Study

Innovation 1: A novel material system of OPMSC self-assembling drug-loaded nanogels

Innovation 2: Aerosol-Flow-Controlled Three-Dimensional Nano-Stacking Fabrication

Innovative 3‑zone precision printing process for neural probes

Innovation in the Design of a Long-Acting, Sustained-Release Drug Delivery Formulation

Innovation 5: Mechanically Matched Additive Manufacturing Interface for Brain Tissue

IV. Existing Process Challenges and Corresponding Solutions for Overcoming Them

Challenge 1: Conventional dip‑coating or spin‑coating covers the metal electrodes, obstructing the acquisition of neural electrical signals.

Challenge 2: Drug‑loaded biomaterials lose activity when exposed to high temperatures or chemical treatments.

Challenge 3: The nano‑gel coating is easily washed away by bodily fluids, leading to short‑term failure.

Challenge 4: Most drug‑eluting coatings exhibit an initial burst release of the therapeutic agent, followed by a lack of anti‑inflammatory efficacy in the later stages.

Challenge 5: Conventional coated films are dense and free of pores, resulting in insufficient drug release pathways.

V. Future Diversified Industrial Application Scenarios

1. Long-term brain-computer interface implantable probe

2. Microelectrodes for Basic Neuroscience Animal Experiments

3. Peripheral Nerve Repair Implantable Devices

4. Minimally Invasive Deep Brain Stimulation Medical Device

5. Next-Generation Flexible Cortical EEG Array

Figure 1. a) Schematic illustration of the formation mechanism of a nanogel-based membrane, which involves the self-assembly of N,O‑carboxylated chitosan (OPMSC) modified with opsonin‑incorporated amphiphilic polydimethylsiloxane, followed by hydrogel crosslinking mediated by the opsonin. TEM images show the network structures of b) PMSC and c) OPMSC spherical nanogels. d) Aerosol jet printing was used to directly pattern an OPMSC suspension onto the surface of neural probes, thereby constructing an anti‑inflammatory neural interface. e) Top‑view and cross‑sectional SEM images confirm that, following aerosol jet printing, the OPMSC nanogel can self‑assemble into a membranous structure. f) AFM topography maps reveal that the OPMSC hydrogel exhibits nanoscale roughness.

Figure 2. a) Mechanical properties of OPMSC hydrogels containing 0%, 1%, 5%, 10%, and 20% OPC, obtained via strain–stress measurements, demonstrating their rubbery elasticity; b) Representative fluorescence microscopy images (10× magnification) showing that CTXT‑NA2 cells preferentially adhere to the flat surface rather than to PMSC and OPMSC substrates (scale bar: 100 µm); c) Relative cell adhesion rates of OPMSC membranes with varying OPC contents, presented as mean ± standard deviation; d) Weight retention of OPMSC materials containing 0%, 1%, 5%, 10%, and 20% OPC after six months of in vitro enzymatic degradation; e) Cell viability of PC12 cells incubated with OPMSC suspensions for one, two, and three days; OPMSCs containing 10% and 20% OPC significantly promoted cell proliferation; f) ROS production levels after 24-hour incubation of PC12 cells with OPMSC suspensions; the lower fluorescence intensity observed in OPMSC samples indicates that OPC exerts an inhibitory effect on intracellular ROS generation, with this inhibitory effect becoming more pronounced as OPC content increases (*P<0.05 vs. control).

Figure 3. a) Optical microscopy (OM) images showing the patterned morphology of PMSC and OPMSC arrays, with a thickness of approximately 30 µm, fabricated via aerosol jet printing (scale bar = 100 µm). Red arrows indicate the locations of the patterns. In contrast, b) the distribution of PC12 cells on the PMSC array and c) on the OPMSC array demonstrates that OPMSCs can maintain structural stability within a biological microenvironment (scale bar = 100 µm). d) Overview and scanning electron microscopy (SEM) image of a flexible OPMSC-coated polyimide (PI) probe (length = 1.48 cm). e) SEM image revealing a cross-sectional view of the OPMSC-coated probe after water washing. f) OPC release profiles of PMSC- and OPMSC-coated probes under pH 7.4 conditions. g) SEM image of PC12 cells grown on an OPMSC-coated neural probe; magnified views show that PC12 cells proliferate exclusively at the sites of the gold microelectrodes.

Figure 4. a) Experimental setup for electrophysiological recordings; b) Changes in signal-to-noise ratio (SNR) and average detection rate across multiple single-neuron units at different time points. Data are presented as mean ± standard deviation. (A) When comparing the SNR of neural recordings obtained with OPMSC-coated versus uncoated probes, the OPMSC-coated probe group exhibited significantly higher SNR on days 14 and 28 than the uncoated probe group on the same days (N=10; *P<0.05). Similarly, when comparing the detection rates of microelectrodes implanted with OPMSC-coated versus uncoated probes, the OPMSC-coated group showed a significantly greater proportion of signals derived from identifiable single-neuron units on days 14 and 28 compared to the uncoated group on the same days (N=10; †P<0.05). c–h) Representative fluorescence images illustrating tissue responses around the tips of uncoated and OPMSC-coated probes at days 2, 7, 14, and 28 post-implantation: (c) ED1 staining; (e) GFAP staining; (g) NeuN staining (scale bar = 100 µm). Quantitative analysis of fluorescence intensity—assessed via ED1 staining (d), GFAP staining (f), and NeuN staining (h)—was used to calculate the integrated fluorescence intensity within a 0–100 µm region surrounding the microelectrode (*P<0.05, post hoc paired t-test).